EP2074095B1 - Procede de preparation d'imatinib et d'intermediaires correspondants - Google Patents

Procede de preparation d'imatinib et d'intermediaires correspondants Download PDF

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EP2074095B1
EP2074095B1 EP07849757.5A EP07849757A EP2074095B1 EP 2074095 B1 EP2074095 B1 EP 2074095B1 EP 07849757 A EP07849757 A EP 07849757A EP 2074095 B1 EP2074095 B1 EP 2074095B1
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Prior art keywords
formula
methyl
phenyl
group
amino
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EP2074095A2 (fr
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Alessandro Falchi
Ennio Grendele
Riccardo Motterle
Mariano Stivanello
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Fabbrica Italiana Sintetici SpA (FIS)
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Priority claimed from ITMI20070942 external-priority patent/ITMI20070942A1/it
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/58—Amidines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D213/00—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members
    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/24—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D213/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C07D213/55—Acids; Esters
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/582—Recycling of unreacted starting or intermediate materials

Definitions

  • Imatinib mesylate a molecule of Formula 9, is an important drug employed in the treatment of the chronic myeloid leukaemia.
  • the technical problem to be solved in view of the prior art is therefore to provide a process for the preparation of 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine and analogues thereof which proceeds with high yields, is easily able of being produced on industrial scale, and economically advantageous.
  • the present invention relates to the preparation of 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine and analogues thereof starting from ⁇ -oxo-3-pyridinpropanal, a salt thereof, or a enolether thereof, or from the ⁇ -oxo-3-pyridinepropionic acid O an ester thereof.
  • R 1 is a NH(CO)R 3 group, in which R 3 represents 4-[(4-methyl-1-piperazinyl)methyl]phenyl
  • the above-described synthesis will directly yield Imatinib.
  • the reaction of cyclization b) requires the use of a base, preferably selected from the group consisting of sodium hydroxide, sodium carbonate, sodium C 1 -C 4 alcoholates, potassium hydroxide, potassium carbonate, potassium C 1 -C 4 alcoholates, lithium hydroxide, lithium carbonate, lithium C 1 -C 4 alcoholates, caesium hydroxide, caesium carbonate, ammonia, and 4-dimethylaminopyridine, more preferably it is potassium hydroxide.
  • the base can be absent in the step a), or it can be present even in the step a).
  • the above-described process comprises the optional step of isolation of the intermediate of Formula 19 , provided that the step a) is not performed in the presence of the base employed in the step b); in this case, the intermediate 19 is achieved with high yield and purity.
  • the synthesis is preferably carried out in a solvent selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, dimethyl sulfoxide, dimethyl formamide, dimethyl acetamide, N-methylpyrrolidone, toluene, and mixtures thereof, more preferably isopropanol.
  • the step a) is preferably carried out at a temperature ranging between 0° C and 50° C and in a time period between 2 and 6 hours, and the step b) preferably at a temperature ranging between 80° C and 140° C and in a time period between 6 and 24 hours.
  • a particularly preferred embodiment of the invention is a process for the preparation of 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine of Formula 8 comprising the steps of
  • the raw 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine is suitably crystallized from toluene in a 80% yield and purity above 99% (HPLC). Such quality of product is employed in the synthesis of Imatinib described in EP 564409 .
  • the ⁇ -oxo-3-pyridinepropanal, or a enolether thereof, of Formula 17 is suitably generated by the addition of an acid to the salt of the ⁇ -oxo-3-pyridinepropanal 18 in which Z represents an alkaline or earth-alkaline metal, preferably sodium or potassium.
  • Z represents an alkaline or earth-alkaline metal, preferably sodium or potassium.
  • R 2 in the compounds of Formula 17 is different from hydrogen, the solvent employed for their preparation is the alcohol of Formula R 2 OH.
  • the acid is preferably hydrochloric acid or acetic acid.
  • the sodium salt of the ⁇ -oxo-3-pyridinepropanal of Formula 20 and the analogues thereof of Formula 18 can be prepared according to the teachings of DE 2125310 , and can be isolated or employed 'in situ'.
  • the (2-methyl-5-aminophenyl)guanidine of Formula 21 and the analogues thereof of Formula 3 can be prepared according to the teachings of WO 2004110452 .
  • a further aspect of the present invention consists in a second process for the preparation of 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine and analogues thereof starting from the ⁇ -oxo-3-pyridinepropionic acid or an ester thereof.
  • the compound of Formula 1' (indicated above in the enolic form) can be under a tautomeric ketonic form.
  • the reaction is preferably carried out in a solvent selected from the group consisting of dimethylformamide, N-methylpyrrolidone, isopropanol, 2-methoxyethyl ether, dimethyl sulfoxide, more preferably in N-methylpyrrolidone, at a temperature preferably ranging between 100° C and 160° C and in a time period preferably ranging between 6 and 18 hours.
  • a solvent selected from the group consisting of dimethylformamide, N-methylpyrrolidone, isopropanol, 2-methoxyethyl ether, dimethyl sulfoxide, more preferably in N-methylpyrrolidone, at a temperature preferably ranging between 100° C and 160° C and in a time period preferably ranging between 6 and 18 hours.
  • the reaction is promoted by using high temperatures, which allow the progress of the condensation and the distilling off of the alcohol, water, and the by-products which form during the reaction.
  • the ⁇ -oxo-3-pyridinepropionic acid or an ester thereof of Formula 2 is preferably employed in a molar ratio ranging between 1,2 : 1 and 2 : 1 in relation to the aryl guanidine of Formula 3.
  • the ethyl ⁇ -oxo-3-pyridine propionate 5 and, by analogy, the compounds of Formula 2 can be prepared according to the teachings of Arch. Pharm., 291, 12-22 (1958 ) and J. Am. Chem. Soc., 63, 490-492 (1941 ).
  • the above-described process comprises the optional halogenation step in order to prepare the compounds of Formula 1', in which X represents chlorine, bromine, or iodine, and R 1 has the foregoing meaning, comprising the reaction of the compounds of Formula 1', in which X represents hydroxyl, or OR 5 , and R 5 has the foregoing meaning, with a halogenating agent.
  • the halogenating agent is preferably selected from the group consisting of phosphorous oxychloride, phosphorous trichloride, phosphorous pentachloride, thionyl chloride, phosphorous oxybromide, phosphorous tribromide, phosphorous pentabromide, and phosphorous triiodide, more preferably it is phosphorous oxychloride.
  • the reaction is promoted by the use of a base, preferably selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, caesium hydroxide, caesium carbonate, caesium bicarbonate, more preferably potassium carbonate, preferably added in amounts of 1-3 equivalents.
  • a base preferably selected from the group consisting of sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, caesium hydroxide, caesium carbonate, caesium bicarbonate, more preferably potassium carbonate, preferably added in amounts of 1-3 equivalents.
  • the reaction is preferably carried out in a solvent selected from toluene and xylene, or in the absence of a solvent, more preferably in the absence of a solvent.
  • the reaction is preferably carried out at a temperature ranging between 20° C and 100° C and in a time period between 3 and 18 hours.
  • the reaction is promoted by the use of the halogenating agent in excess relative to the compound of Formula 1', preferably in a molar ratio between 8 : 1 and 20 : 1; such excess of reagent promotes the progress of the reaction, and it can be subsequently recovered by reduced-pressure distillation.
  • the compound of Formula 1' in which X represents chlorine, bromine, or iodine, can be purified by crystallization or crushing from one or more solvents preferably selected from the group consisting of water, toluene, xylene, ethyl acetate, isopropyl acetate and isopropanol, more preferably from water and toluene.
  • solvents preferably selected from the group consisting of water, toluene, xylene, ethyl acetate, isopropyl acetate and isopropanol, more preferably from water and toluene.
  • the above-described process comprises the optional reduction step in order to prepare the compounds of Formula 1' , in which X represents hydrogen, and R 1 has the foregoing meaning, comprising the reaction of the compounds of Formula 1' , in which X represents chlorine, bromine, or iodine, or -OSO 2 R 6 , where R 6 has the foregoing meaning, with a reducing agent.
  • R 1 represents a nitro group
  • the reduction allows concomitantly performing the removal of the halogen from the pyrimidine ring and the reduction of the nitro group to amino of the benzenic ring.
  • a particularly preferred embodiment here described is a process for the preparation of 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine of Formula 8 comprising the reaction of the 6-chloro-N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of Formula 7 with a reducing agent.
  • the reducing agent is preferably selected from the group consisting of hydrogen, cyclohexadiene, ammonium formate, tin dichloride, tin, nickel chloride, nickel, lithium aluminium hydride, sodium aluminium hydride, sodium hydrosulfite, more preferably it is hydrogen.
  • the reaction is carried out in the presence of a catalyst, preferably based on palladium or nickel, more preferably selected from the group consisting of palladium on carbon, palladium on barium sulphate, and palladium on calcium carbonate.
  • the catalyst is preferably employed in amounts between 0.02 and 0.1 in moles relative to the compound to be reduced.
  • the reaction is preferably carried out in the presence of a base, preferably selected from the group consisting of triethylamine, pyridine, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, caesium hydroxide, caesium carbonate, caesium bicarbonate, more preferably it is triethylamine.
  • a base preferably selected from the group consisting of triethylamine, pyridine, sodium hydroxide, sodium carbonate, sodium bicarbonate, potassium hydroxide, potassium carbonate, potassium bicarbonate, caesium hydroxide, caesium carbonate, caesium bicarbonate, more preferably it is triethylamine.
  • the reduction is preferably carried out in a solvent selected from the group consisting of ethanol, methanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran and dimethylformamide, more preferably in ethanol, it is preferably carried out at a temperature ranging between 20 and 80° C and in a time period between 2 and 18 hours.
  • a solvent selected from the group consisting of ethanol, methanol, isopropanol, ethyl acetate, isopropyl acetate, tetrahydrofuran and dimethylformamide
  • the compound of Formula 1' employed as a reagent, in which X represents chlorine, bromine, or iodine, can be used as the free base, or as a salt.
  • the addition of the above-described base allows neutralizing the acid which forms during the reaction, and solubilize the reagent of Formula 1', if this is in the salt form.
  • the compound of Formula 1' achieved by the reduction, in which X represents hydrogen, is suitably purified by crystallization, preferably from toluene or methanol.
  • the step reduction can be performed before the halogenation step.
  • the above-described process comprises the optional reduction step in order to prepare the compounds of Formula 1' , in which R 1 represents an amino group and X represents hydroxy or OR 5 , and R 5 has the foregoing meaning, comprising the reaction of the compounds of Formula 1' , in which R 1 represents a nitro group, with a reducing agent.
  • R 1 represents an amino group
  • R 5 represents a nitro group
  • a further reduction step follows the halogenation step in order to remove the X group.
  • R 1 represents a NHR 4 group, in which R 4 represents a protecting group for the amine group, or X represents a OR 5 group, in which R 5 represents an activating group for the hydroxyl group
  • R 4 represents a protecting group for the amine group
  • X represents a OR 5 group
  • R 5 represents an activating group for the hydroxyl group
  • the synthesis process for the compounds of Formula 1' comprises the reaction of the compounds of Formula 1' , in which X represents hydroxy, with a sulfonilating agent, preferably R 6 SO 2 Y, in which Y represents chlorine, bromine, iodine, -OSO 2 R 6 .
  • R 1 is a NH(CO)R 3 group, in which R 3 represents 4-(halo-methyl)phenyl, 4-(hydroxymethyl)phenyl, 4-((4-methylpiperazinyl)carbonyl)phenyl, 4-(alkoxycarbonyl)phenyl, in which alkoxy means C 1 -C 4 alkoxy
  • the above-described synthesis will yield a more advanced intermediate in the synthesis of Imatinib compared to the 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine compound of Formula 8 .
  • R 1 is a NH(CO)R 3 group, in which R 3 represents 4-[(4-methyl-1-piperazinyl)methyl]phenyl
  • the above-described synthesis will directly yield Imatinib.
  • a further aspect of the present invention consists in a third process for the preparation of 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine and analogues thereof starting from the ⁇ -oxo-3-pyridinepropionic acid or an ester thereof.
  • step a) is preferably, but not necessarily, performed in the presence of an anhydride or an acid.
  • the anhydride is preferably acetic anhydride, and the acid is preferably selected from the group consisting of pyridinium p -toluenesulfonate, dry hydrochloric acid, dry hydrobromic acid, sulforic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid, p -toluenesulfonic acid, more preferably it is pyridinium p -toluenesulfonate.
  • the anhydride is preferably employed in an amount ranging between 1 and 3 equivalents, while the acid is preferably employed in amounts ranging between 0.001 and 0.1 equivalents relative to the compound of Formula 2 .
  • the orthoformate is preferably employed as a solvent, with an excess between 1 and 6 volumes relative to the compound of Formula 2 , and the excess can be recovered at the end of the reaction by distillation.
  • the reaction is preferably carried out at a temperature between 100° C and 140° C and in a time period between 1 and 5 hours, by distillating the R 7 OH alcohol which develops during the condensation.
  • the ethyl ⁇ -(etoxymethylene)- ⁇ -oxo-3-pyridine propionate compound of Formula 12 is generally achieved in quantitative yield and with purity above 80%. Such quality of product is employed in the step b).
  • the step b) is preferably carried out in a high-boiling organic solvent, preferably selected from the group consisting of toluene, xylene, chlorobenzene, dimethyl sulfoxide, N-methylpyrrolidone, isopropyl acetate, still more preferably in toluene.
  • the reaction is preferably carried out at a temperature ranging between 100° C and 150° C in a time period between 30 minutes and 5 hours, by distilling off the alcohol and water which form during the reaction.
  • the compound of Formula 10 is preferably employed in molar excess relative to the aryl guanidine of Formula 3 .
  • the compound of Formula 11 can be isolated at the end of the reaction by cooling the reaction mixture and filtrating the crystallized product.
  • the ethyl 2-[(2-methyl-5-nitrophenyl)amino]-4-pyridine-3-yl-pyrimidine-5-carboxylate 14 is achieved in yield above 85% and purity above 97% (HPLC).
  • the step c) preferably comprises the steps of
  • the hydrolysis step c1) can be performed both in the presence of an acid, and in the presence of a base.
  • the acid is preferably a mineral acid, preferably selected from the group consisting of sulforic, hydrochloric, bromhydric, and percloric acid, preferably it is hydrochloric acid.
  • the base is preferably an inorganic base, preferably selected from sodium carbonate, sodium hydroxide, potassium carbonate, potassium hydroxide, lithium carbonate, lithium hydroxide, more preferably sodium carbonate, and it is preferably employed in a molar ratio between 1 : 1 and 3 : 1 relative to the ester of Formula 11 .
  • the step c1) is preferably carried out in water or an alcohol, or mixtures thereof.
  • the alcohol is preferably selected from the group consisting of methanol, ethanol, isopropanol, more preferably it is ethanol.
  • the reaction is preferably carried out at a temperature between 80 and 100° C, in a time period between 1 and 18 hours, and in distillation conditions suitable to complete the conversion.
  • the compounds of Formula 15 can be isolated by cooling the reaction mixture and, in the case of using a base in order to perform the hydrolysis, by acidifying the reaction mixture with an acid, achieving the product precipitation as a crystalline solid which can be regenerated by filtration.
  • a base in order to perform the hydrolysis
  • acidifying the reaction mixture with an acid achieving the product precipitation as a crystalline solid which can be regenerated by filtration.
  • the 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylic acid of Formula 16 is achieved in a yield above 95% and purity above 95%.
  • the decarboxylation step c2) is preferably carried out at high temperature and in the presence of an acid, as for the step c1), or in the presence of a cupper-based catalyst, preferably selected from the group consisting of metallic cupper and cupper(II) oxide, more preferably cupper(II) oxide.
  • the catalyst is preferably employed in amounts between 0.01 and 0.1 moles relative to the reagent of Formula 15 . The employment of the cupper allows for a better progress of the reaction, minimizing degradation side-reaction.
  • the decarboxylation is preferably carried out in a solvent selected from the group consisting of quinoline, N-methylpyrrolidone, and sulfolane, still more preferably in N-methylpyrrolidone.
  • the reaction is preferably carried out at a temperature between 160 and 200° C and in a time period between 0.5 and 4 hours.
  • the steps c1) and c2) can be carried out in the same reaction conditions by processing the compounds of Formula 11 with an acid, preferably with hydrochloric acid.
  • N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine of Formula 13 is achieved, following basification and filtration, in quantitative yield and purity above 95%. Such quality of product is employed in the synthesis of the Imatinib and the analogues thereof described in EP 564409 .
  • the present invention provides a simple method for the production of 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine and the analogues thereof, having the following advantages:
  • Example 4 (not within the present invention): ethyl ⁇ -(etoxymethylene)- ⁇ -oxo-3-pyridine propionate 12
  • Example 5 (not within the present invention): ethyl 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylate 14
  • Example 6 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylic acid 16
  • Example 7 N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2-pyrimidine amine 13
  • Example 8 N-(2-methyl-5-nitrophenyl)-4-(3-pyridinyl)-2 pyrimidine amine 13
  • 140 g ethyl 2- [(2-methyl-5-nitrophenyl) amino] -4- (3-pyridinyl)pyrimidine-5-carboxylate and 109 g potassium carbonate is suspended in a mixture composed by 1050 mL water and 560 mL ethanol. The mixture is refluxed for 1 hour, then 700 mL solvent are slowly distilled. Once completed the conversion, the mixture is cooled to 80° C and it is adjusted to pH a 7 with 95 mL acetic acid. 560 mL N-methylpyrrolidone and 0.9 g CuO is added. The water present is distilled under reduced pressure, and the mixture is heated to 175-180° C for 2 hours.
  • the mixture is cooled to 80-90° C, 1000 mL water and 5 g EDTA is slowly added, the mixture is stirred at room temperature, the product is filtrated and washed with water. Upon drying, 108 g of product with HPLC purity of 95% (A%) is achieved. This can be recrystallized from 10 volumes of 95:5 xylene/N-methylpyrrolidone to yield a product with 98% purity (A%) in a 80% yield.
  • Example 9 sodium 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylate
  • Example 10 (not within the present invention): ethyl ⁇ -(etoxymethylene)- ⁇ -oxo-3-pyridine propionate 12
  • Example 11 6-hydroxy-N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine 4
  • Example 12 6-chloro-N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine 7
  • Such raw product also contains a by-product, in an amount of about 15% (A%) which, during the following reduction reaction, still yields the desired product (4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine).
  • the raw material therefore, is employed as is in the example 13.
  • Example 13 4-methyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzenediamine 8
  • 5 g 6-chloro-N-(2-methyl-5-nitrophenyl)-4-(3-pyridyl)-2-pyrimidine amine 0.5 g palladium on charcoal 5% wet with 50% water, 50 mL ethanol and 5 mL triethylamine is charged.
  • the mixture is hydrogenated at 5 bars and room temperature for 40 hours.
  • the catalyst is filtered off and the filtrates is concentrated in vacuum. The residue is taken again with isopropyl acetate and an aqueous carbonate solution.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pyridine Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Claims (14)

  1. Procédé pour la préparation de composés de formule 1
    Figure imgb0055
    où R1 représente amino, nitro, halogène, hydroxy, NH(CO)R3, NHR4,
    R3 représente 4-(halo-méthyl)phényle, 4-(hydroxyméthyl)-phényle, 4-((4-méthylpipérazinyl)carbonyl)phényle, 4-(alcoxycarbonyl)-phényle ou 4-[(4-méthyl-1-pipérazinyl)méthyl]phényle, où alcoxy signifie C1-C4 alcoxy,
    R4 représente un groupe protecteur pour le groupe amino,
    comprenant les étapes de :
    a) réaction du β-oxo-3-pyridinepropanal, d'un sel de celui-ci ou d'un énoléther de celui-ci de formule 17
    Figure imgb0056
     où R2 représente l'hydrogène, C1-C4-alkyle, benzyle ou phényle,
    avec une arylguanidine de formule 3
    Figure imgb0057
     où R1 a la signification décrite ci-dessus, pour produire le composé de formule 19
    Figure imgb0058
     où R1 a la signification précédente, et
    b) cyclisation de l'intermédiaire de formule 19 en présence d'une base.
  2. Procédé selon la revendication 1, où R1 représente amino, nitro, NH(CO)R3, NHR4, de préférence amino ou nitro.
  3. Procédé selon les revendications 1-2, où R2 représente l'hydrogène, isopropyle ou n-butyle.
  4. Procédé selon les revendications 1-3, où R3 représente 4-(chlorométhyl)phényle ou 4-[(4-méthyl-1-pipérazinyl)méthyl]phényle.
  5. Procédé selon les revendications 1-4, où R4 représente un carboxamide, un sulfonamide ou un carbamate, de préférence il représente un groupe COCH3, (CO)OBn, (CO)-O-t-Bu, (SO2) Ph, (SO2) (4-Me-Ph).
  6. Procédé selon les revendications 1-5, où la base employée dans l'étape b) est choisie dans le groupe consistant en l'hydroxyde de sodium, le carbonate de sodium, les C1-C4 alcoolates de sodium, l'hydroxyde de potassium, le carbonate de potassium, les C1-C4 alcoolates de potassium, l'hydroxyde de lithium, le carbonate de lithium, les C1-C4 alcoolates de lithium, l'hydroxyde de césium, le carbonate de césium, l'ammoniac et la 4-diméthylaminopyridine, de préférence c'est l'hydroxyde de potassium.
  7. Procédé selon les revendications 1-6, où ladite base est présente aussi dans l'étape a).
  8. Procédé selon les revendications 1-6, où ladite base est absente dans l'étape a), et comprenant l'étape d'isolement de l'intermédiaire de formule 19.
  9. Procédé selon les revendications 1-8, où la synthèse est conduite dans un solvant choisi dans le groupe consistant en le méthanol, l'éthanol, l'isopropanol, le n-butanol, le diméthylsulfoxyde, le diméthylformamide, le diméthylacétamide, la N-méthylpyrrolidone, le toluène, et leurs mélanges, de préférence l'isopropanol.
  10. Procédé pour la préparation de la 4-méthyl-N3-[4-(3-pyridinyl)-2-pyrimidinyl]-1,3-benzénediamine de formule 8
    Figure imgb0059
     comprenant les étapes de :
    a) réaction du sel de sodium du β-oxo-3-pyridinepropanal de formule 20 (ou d'un tautomère de celui-ci)
    Figure imgb0060
     avec la (2-méthyl-5-aminophényl)guanidine de formule 21
    Figure imgb0061
     pour produire le composé de formule 22
    Figure imgb0062
    et b) cyclisation de l'intermédiaire de formule 22 en présence d'une base.
  11. Composés de formule 19
    Figure imgb0063
    où R1 représente amino, nitro, halogène, hydroxy, NH(CO)R3, NHR4,
    R3 représente 4-(halo-méthyl)phényle, 4-(hydroxyméthyl)-phényle, 4-((4-méthylpipérazinyl)carbonyl)phényle, 4-(alcoxycarbonyl)-phényle ou 4-[(4-méthyl-1-pipérazinyl)méthyl]phényle, où alcoxy signifie C1-C4 alcoxy, et
    R4 représente un groupe protecteur pour le groupe amine.
  12. Composés selon la revendication 11, où R1 représente amino, nitro, NH(CO)R3, NHR4, de préférence amino ou nitro, de préférence encore amino.
  13. Composés selon les revendications 11-12, où R3 représente 4-(chlorométhyl)phényle, ou 4-[(4-méthyl-1-pipérazinyl)méthyl]phényle.
  14. Composés selon les revendications 11-13, où R4 représente un carboxamide, un sulfonamide ou un carbamate, de préférence représente un groupe COCH3, (CO)OBn, (CO)O-t-Bu, (SO2)Ph, (SO2) (4-Me-Ph).
EP07849757.5A 2006-11-16 2007-11-15 Procede de preparation d'imatinib et d'intermediaires correspondants Not-in-force EP2074095B1 (fr)

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PCT/IT2007/000804 WO2008059551A2 (fr) 2006-11-16 2007-11-15 Procédé de préparation d'imatinib et d'intermédiaires correspondants

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JP5265562B2 (ja) * 2006-11-16 2013-08-14 エッフェ．イー．エッセ． ファブリカ イタリアーナ シンテーティチ エッセ．ペー．アー． イマチニブおよびその中間体の調製方法
PL215042B1 (pl) * 2008-08-01 2013-10-31 Temapharm Spolka Z Ograniczona Odpowiedzialnoscia Sposób wytwarzania imatinibu
WO2011157450A1 (fr) 2010-06-18 2011-12-22 Krka, D. D., Novo Mesto Nouvelle forme polymorphique d'imatinib base et préparation de ses sels
ITMI20111309A1 (it) 2011-07-14 2013-01-15 Italiana Sint Spa Procedimento di preparazione di imatinib mesilato
GB2514285B (en) 2012-02-13 2018-07-18 Grindeks Jsc Intermediates for a novel process of preparing imatinib and related tyrosine kinase inhibitors
WO2013171102A1 (fr) * 2012-05-16 2013-11-21 Solvay Sa Fabrication de composés de méthylidène 1-substitués
WO2014015157A2 (fr) 2012-07-19 2014-01-23 Philadelphia Health & Education Corporation Nouveaux ligands du récepteur sigma et procédés de modulation de l'homéostase de protéine cellulaire à l'aide de ceux-ci
EP2927223B1 (fr) 2014-04-04 2016-06-29 F.I.S.- Fabbrica Italiana Sintetici S.p.A. Procédé de préparation de l'imatinib et de ses sels, exempt d'impureté génotoxique f
CN104003944B (zh) * 2014-05-29 2016-08-24 西北师范大学 一种嘧菌胺的制备方法
US11117870B2 (en) 2017-11-01 2021-09-14 Drexel University Compounds, compositions, and methods for treating diseases

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US20050032869A1 (en) 2003-07-08 2005-02-10 Pharmacia Italia S.P.A. Pyrazolyl-indole derivatives active as kinase inhibitors, process for their preparation and pharmaceutical compositions comprising them
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US8168787B2 (en) 2012-05-01
US20100076189A1 (en) 2010-03-25
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KR20090083455A (ko) 2009-08-03
BRPI0718812A2 (pt) 2013-12-03
US8334381B2 (en) 2012-12-18

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